{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:29:05Z","timestamp":1794047345131,"version":"4.8.0"},"reference-count":61,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"3","license":[{"start":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T00:00:00Z","timestamp":1578528000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/legalcode"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>Trypanosomiasis is a parasitic disease, affecting both humans and animals, in the form of Human African Trypanosomiasis and Nagana disease, respectively. Anemia is one of the most common symptoms of trypanosomiasis, and if left unchecked, can cause severe complications and even death. Several factors have been associated with the development of this anemia, including dysregulation of iron homeostasis, but little is known about the molecular mechanisms involved. Here, using murine models, we study the involvement of hepcidin, the key regulator of iron metabolism and an important player in the development of anemia of inflammation. Our data shows two stages for the progression of anemia, to which hepcidin contributes: a first stage, when anemia develops, with a likely cytokine-mediated stimulation of hepcidin and subsequent limitation in iron availability and erythropoiesis, and a second stage, of recovery, where hepcidin elevation declines due to the decreased inflammatory signal and increased production of erythroid regulators by the kidney, spleen and bone marrow, thus leading to an increase in iron release and availability and enhanced erythropoiesis. In agreement, in hepcidin knockout mice, anaemia is much milder and its recovery is complete, in contrast to wild-type animals which do not fully recover from anaemia after 21 days. Aside from all other factors known to be involved in the development of anemia during trypanosomiasis, there clearly is an important contribution of hepcidin for both its development and recovery.<\/jats:p>","DOI":"10.3324\/haematol.2019.227728","type":"journal-article","created":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T12:15:23Z","timestamp":1578572123000},"page":"806-818","source":"Crossref","is-referenced-by-count":10,"title":["A role for hepcidin in the anemia caused by Trypanosoma brucei infection"],"prefix":"10.3324","volume":"106","author":[{"family":"Jo\u00e3o V. Neves","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Ana C. Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"David M. Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Carolina Barroso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Sophie Vaulont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Anabela Cordeiro da Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Joana Tavares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Pedro N.S. Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2020,1,9]]},"reference":[{"key":"22526","doi-asserted-by":"crossref","unstructured":"Aksoy S, Buscher P, Lehane M, Solano P, Van Den Abbeele J. Human African trypanosomiasis control: Achievements and challenges. PLoS Negl Tro Dis. 2017; 11(4):e0005454.","DOI":"10.1371\/journal.pntd.0005454"},{"key":"22527","doi-asserted-by":"crossref","unstructured":"Courtin D, Berthier D, Thevenon S, Dayo GK, Garcia A, Bucheton B. Host genetics in African trypanosomiasis. Infecti Genet Evol. 2008; 8(3):229-238.","DOI":"10.1016\/j.meegid.2008.02.007"},{"key":"22528","doi-asserted-by":"crossref","unstructured":"Amole BO, Clarkson AB, Shear HL. Pathogenesis of anemia in Trypanosoma brucei-infected mice. Infect Immun. 1982; 36(3):1060-1068.","DOI":"10.1128\/IAI.36.3.1060-1068.1982"},{"key":"22529","doi-asserted-by":"crossref","unstructured":"Cox FE. Pathogenesis of animal trypanosomiasis. Nature. 1979; 277(5698):603-604.","DOI":"10.1038\/277603a0"},{"key":"22530","doi-asserted-by":"crossref","unstructured":"Murray M, Dexter TM. Anaemia in bovine African trypanosomiasis. A review. Acta Trop. 1988; 45(4):389-432.","DOI":"10.1002\/j.1834-4453.1988.tb00198.x"},{"key":"22531","doi-asserted-by":"crossref","unstructured":"d'Ieteren GD, Authie E, Wissocq N, Murray M. Trypanotolerance, an option for sustainable livestock production in areas at risk from trypanosomosis. Rev Sci Tech. 1998; 17(1):154-175.","DOI":"10.20506\/rst.17.1.1088"},{"key":"22532","unstructured":"Mbaya A, Kumshe H, Nwosu CO. The mechanisms of anaemia in Trypanosomiasis: a review. 2010;269-82."},{"key":"22533","doi-asserted-by":"crossref","unstructured":"Stijlemans B, Cnops J, Naniima P. Development of a pHrodo-based assay for the assessment of in vitro and in vivo erythrophagocytosis during experimental trypanosomosis. PLoS Negl Trop Dis. 2015; 9(3):e0003561.","DOI":"10.1371\/journal.pntd.0003561"},{"key":"22534","doi-asserted-by":"crossref","unstructured":"Stijlemans B, De Baetselier P, Magez S, Van Ginderachter JA, De Trez C. African Trypanosomiasis-associated anemia: the contribution of the interplay between parasites and the mononuclear phagocyte system. Front Immunol. 2018; 9:218.","DOI":"10.3389\/fimmu.2018.00218"},{"key":"22535","unstructured":"Huan CN, Webb L, Lambert PH, Miescher PA. Pathogenesis of the anemia in African Trypanosomiasis: characterization and purification of a hemolytic factor. Schweiz Med Wochenschr. 1975; 105(47):1582-1583."},{"key":"22536","doi-asserted-by":"crossref","unstructured":"Tizard IR, Sheppard J, Neilsen K. The characterization of a second class of haemolysins from Trypanosoma brucei. Trans R Soc Trop Med Hyg. 1978; 72(2):198-200.","DOI":"10.1016\/0035-9203(78)90063-9"},{"key":"22537","unstructured":"Vickerman K, Tetley L. Biology and ultastructure of trypanosomes in relation to pathogenesis. 1978;23-31."},{"key":"22538","doi-asserted-by":"crossref","unstructured":"Igbokwe IO, Esievo KA, Saror DI, Obagaiye OK. Increased susceptibility of erythrocytes to in vitro peroxidation in acute Trypanosoma brucei infection of mice. Vet Parasitol. 1994; 55(4):279-286.","DOI":"10.1016\/0304-4017(94)90070-1"},{"key":"22539","doi-asserted-by":"crossref","unstructured":"Umar IA, Ogenyi E, Okodaso D. Amelioration of anaemia and organ damage by combined intraperitoneal administration of vitamins A and C to Trypanosoma brucei brucei-infected rats. Afr J Biotechnol. 2007; 6(18):2083-2086.","DOI":"10.5897\/AJB2007.000-2322"},{"key":"22540","doi-asserted-by":"crossref","unstructured":"Clemens MR, Waller HD. Lipid peroxidation in erythrocytes. Chem Phys Lipids. 1987; 45(2-4):251-268.","DOI":"10.1016\/0009-3084(87)90068-5"},{"key":"22541","doi-asserted-by":"crossref","unstructured":"Szempruch AJ, Sykes SE, Kieft R. Extracellular vesicles from Trypanosoma brucei mediate virulence factor transfer and cause host anemia. Cell. 2016; 164(1-2):246-257.","DOI":"10.1016\/j.cell.2015.11.051"},{"key":"22542","doi-asserted-by":"crossref","unstructured":"Stijlemans B, Beschin A, Magez S, Van Ginderachter JA, De Baetselier P. Iron homeostasis and Trypanosoma brucei associated immunopathogenicity development: a battle\/ quest for iron. Biomed Res Int. 2015; 2015:819389.","DOI":"10.1155\/2015\/819389"},{"key":"22543","doi-asserted-by":"crossref","unstructured":"Stijlemans B, Vankrunkelsven A, Brys L, Magez S, De Baetselier P. Role of iron homeostasis in trypanosomiasis-associated anemia. Immunobiology. 2008; 213(9-10):823-835.","DOI":"10.1016\/j.imbio.2008.07.023"},{"key":"22544","doi-asserted-by":"crossref","unstructured":"Nemeth E, Ganz T. Regulation of iron metabolism by hepcidin. Annu Rev Nutr. 2006; 26:323-342.","DOI":"10.1146\/annurev.nutr.26.061505.111303"},{"key":"22545","doi-asserted-by":"crossref","unstructured":"Ganz T. Hepcidin-a regulator of intestinal iron absorption and iron recycling by macrophages. Best Pract Res Clin Haematol. 2005; 18(2):171-182.","DOI":"10.1016\/j.beha.2004.08.020"},{"key":"22546","doi-asserted-by":"crossref","unstructured":"Ramey G, Deschemin JC, Durel B, Canonne-Hergaux F, Nicolas G, Vaulont S. Hepcidin targets ferroportin for degradation in hepatocytes. Haematologica. 2010; 95(3):501-504.","DOI":"10.3324\/haematol.2009.014399"},{"key":"22547","doi-asserted-by":"crossref","unstructured":"Moreira AC, Neves JV, Silva T, Oliveira P, Gomes MS, Rodrigues PN. Hepcidin- (in)dependent mechanisms of iron metabolism regulation during infection by Listeria and Salmonella. Infect Immun. 2017; 85(9)","DOI":"10.1128\/IAI.00353-17"},{"key":"22548","doi-asserted-by":"crossref","unstructured":"Arezes J, Jung G, Gabayan V. Hepcidininduced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe. 2015; 17(1):47-57.","DOI":"10.1016\/j.chom.2014.12.001"},{"key":"22549","doi-asserted-by":"crossref","unstructured":"Burns M, Muthupalani S, Ge Z. Helicobacter pylori infection induces anemia, depletes serum iron storage, and alters local iron-related and adult brain gene expression in male INS-GAS mice. PLoS One. 2015; 10(11):e0142630.","DOI":"10.1371\/journal.pone.0142630"},{"key":"22550","doi-asserted-by":"crossref","unstructured":"Kim A, Fung E, Parikh SG. A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. Blood. 2014; 123(8):1129-1136.","DOI":"10.1182\/blood-2013-08-521419"},{"key":"22551","doi-asserted-by":"crossref","unstructured":"Gardenghi S, Renaud TM, Meloni A. Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus. Blood. 2014; 123(8):1137-1145.","DOI":"10.1182\/blood-2013-08-521625"},{"key":"22552","doi-asserted-by":"crossref","unstructured":"Ben-Othman R, Flannery AR, Miguel DC, Ward DM, Kaplan J, Andrews NW. Leishmania-mediated inhibition of iron export promotes parasite replication in macrophages. PLoS Pathog. 2014; 10(1):e1003901.","DOI":"10.1371\/journal.ppat.1003901"},{"key":"22553","doi-asserted-by":"crossref","unstructured":"Ferrer P, Castillo-Neyra R, Roy CN, Sullivan DJ. Dynamic control of hepatic Plasmodium numbers by hepcidin despite elevated liver iron during iron supplementation. Microbes Infect. 2016; 18(1):48-56.","DOI":"10.1016\/j.micinf.2015.08.018"},{"key":"22554","doi-asserted-by":"crossref","unstructured":"Lesbordes-Brion JC, Viatte L, Bennoun M. Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Blood. 2006; 108(4):1402-1405.","DOI":"10.1182\/blood-2006-02-003376"},{"key":"22555","unstructured":"Torrence JD, Bothwell TH. Tissue Iron Stores. 1980;104-9."},{"key":"22556","doi-asserted-by":"crossref","unstructured":"McLatchie AP, Burrell-Saward H, Myburgh E. Highly sensitive in vivo imaging of Trypanosoma brucei expressing &quot;red-shifted&quot; luciferase. PLoS Negl Trop Dis. 2013; 7(11):e2571.","DOI":"10.1371\/journal.pntd.0002571"},{"key":"22557","doi-asserted-by":"crossref","unstructured":"Viatte L, Vaulont S. Hepcidin, the iron watcher. Biochimie. 2009; 91(10):1223-1228.","DOI":"10.1016\/j.biochi.2009.06.012"},{"key":"22558","doi-asserted-by":"crossref","unstructured":"Wang W, Knovich MA, Coffman LG, Torti FM, Torti SV. Serum ferritin: past, present and future. Biochim Biophys Acta. 2010; 1800(8):760-769.","DOI":"10.1016\/j.bbagen.2010.03.011"},{"key":"22559","doi-asserted-by":"crossref","unstructured":"Basu S, Horakova E, Lukes J. Iron-associated biology of Trypanosoma brucei. 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Curr Opin Hematol. 2005; 12(2):107-111.","DOI":"10.1097\/00062752-200503000-00001"},{"key":"22564","doi-asserted-by":"crossref","unstructured":"Soares MP, Hamza I. Macrophages and iron metabolism. Immunity. 2016; 44(3):492-504.","DOI":"10.1016\/j.immuni.2016.02.016"},{"key":"22565","doi-asserted-by":"crossref","unstructured":"Nemeth E, Rivera S, Gabayan V. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004; 113(9):1271-1276.","DOI":"10.1172\/JCI200420945"},{"key":"22566","doi-asserted-by":"crossref","unstructured":"Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006; 108(9):3204-3209.","DOI":"10.1182\/blood-2006-06-027631"},{"key":"22567","doi-asserted-by":"crossref","unstructured":"Felli N, Pedini F, Zeuner A. Multiple members of the TNF superfamily contribute to IFN-gamma-mediated inhibition of erythropoiesis. J Immunol. 2005; 175(3):1464-1472.","DOI":"10.4049\/jimmunol.175.3.1464"},{"key":"22568","doi-asserted-by":"crossref","unstructured":"Magez S, Radwanska M, Beschin A, Sekikawa K, De Baetselier P. Tumor necrosis factor alpha is a key mediator in the regulation of experimental Trypanosoma brucei infections. Infect Immun. 1999; 67(6):3128-3132.","DOI":"10.1128\/IAI.67.6.3128-3132.1999"},{"key":"22569","doi-asserted-by":"crossref","unstructured":"Magez S, Schwegmann A, Atkinson R. The role of B-cells and IgM antibodies in parasitemia, anemia, and VSG switching in Trypanosoma brucei-infected mice. PLoS Pathog. 2008; 4(8):e1000122.","DOI":"10.1371\/journal.ppat.1000122"},{"key":"22570","doi-asserted-by":"crossref","unstructured":"Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. 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Front Immunol. 2017; 8:498.","DOI":"10.3389\/fimmu.2017.00498"},{"key":"22581","doi-asserted-by":"crossref","unstructured":"Nemeth E, Tuttle MS, Powelson J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004; 306(5704):2090-2093.","DOI":"10.1126\/science.1104742"},{"key":"22582","doi-asserted-by":"crossref","unstructured":"Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014; 46(7):678-684.","DOI":"10.1038\/ng.2996"},{"key":"22583","doi-asserted-by":"crossref","unstructured":"Arezes J, Foy N, McHugh K. Erythroferrone inhibits the induction of hepcidin by BMP6. Blood. 2018; 132(14):1473-1477.","DOI":"10.1182\/blood-2018-06-857995"},{"key":"22584","doi-asserted-by":"crossref","unstructured":"Kautz L, Jung G, Nemeth E, Ganz T. Erythroferrone contributes to recovery from anemia of inflammation. Blood. 2014; 124(16):2569-2574.","DOI":"10.1182\/blood-2014-06-584607"},{"key":"22585","doi-asserted-by":"crossref","unstructured":"Tanno T, Bhanu NV, Oneal PA. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007; 13(9):1096-1101.","DOI":"10.1038\/nm1629"},{"key":"22586","doi-asserted-by":"crossref","unstructured":"Tanno T, Porayette P, Sripichai O. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. 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